EP0614898A1 - Derive indole, procede pour sa fabrication, et son usage medicinal - Google Patents
Derive indole, procede pour sa fabrication, et son usage medicinal Download PDFInfo
- Publication number
- EP0614898A1 EP0614898A1 EP93921084A EP93921084A EP0614898A1 EP 0614898 A1 EP0614898 A1 EP 0614898A1 EP 93921084 A EP93921084 A EP 93921084A EP 93921084 A EP93921084 A EP 93921084A EP 0614898 A1 EP0614898 A1 EP 0614898A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- epoxy
- didehydro
- indolomorphinan
- dihydroxy
- cyclopropylmethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000002475 indoles Chemical class 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims description 15
- 230000008569 process Effects 0.000 title claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 39
- 239000002253 acid Substances 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 6
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 144
- -1 trifluoromethoxy, cyano, phenyl Chemical group 0.000 claims description 32
- 210000004556 brain Anatomy 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- 150000004031 phenylhydrazines Chemical class 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 101100203602 Hypocrea jecorina (strain QM6a) sor7 gene Proteins 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 5
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- 239000003223 protective agent Substances 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 4
- 239000000043 antiallergic agent Substances 0.000 claims description 4
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229960003444 immunosuppressant agent Drugs 0.000 abstract description 4
- 210000004958 brain cell Anatomy 0.000 abstract description 3
- 230000003266 anti-allergic effect Effects 0.000 abstract description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- 230000001861 immunosuppressant effect Effects 0.000 abstract description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1004
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 502
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 502
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 117
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 85
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 61
- 239000000203 mixture Substances 0.000 description 52
- 239000000243 solution Substances 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 238000004458 analytical method Methods 0.000 description 42
- 230000000694 effects Effects 0.000 description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- SORNZTKTFUGVQA-UHFFFAOYSA-N 2-(3-hydrazinylphenyl)ethanol Chemical compound NNC1=CC=CC(CCO)=C1 SORNZTKTFUGVQA-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 150000002431 hydrogen Chemical group 0.000 description 19
- 230000009471 action Effects 0.000 description 18
- 241000699666 Mus <mouse, genus> Species 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 239000005557 antagonist Substances 0.000 description 16
- 230000006698 induction Effects 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 15
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 15
- 229940098779 methanesulfonic acid Drugs 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 230000001629 suppression Effects 0.000 description 15
- 230000005951 type IV hypersensitivity Effects 0.000 description 15
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 15
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- 229960003086 naltrexone Drugs 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000857 delta opiate receptor antagonist Substances 0.000 description 12
- UFWAWZMOTPGQJU-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-1-ylhydrazine Chemical compound C1CCCC2=C1C=CC=C2NN UFWAWZMOTPGQJU-UHFFFAOYSA-N 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 235000011054 acetic acid Nutrition 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 206010070834 Sensitisation Diseases 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 150000002429 hydrazines Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 230000008313 sensitization Effects 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 210000004989 spleen cell Anatomy 0.000 description 9
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 8
- 108700023159 delta Opioid Receptors Proteins 0.000 description 8
- 102000048124 delta Opioid Receptors Human genes 0.000 description 8
- 229960004127 naloxone Drugs 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 7
- 230000001506 immunosuppresive effect Effects 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 108700022182 D-Penicillamine (2,5)- Enkephalin Proteins 0.000 description 6
- MCMMCRYPQBNCPH-WMIMKTLMSA-N DPDPE Chemical compound C([C@H](N)C(=O)N[C@@H]1C(C)(C)SSC([C@@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)CNC1=O)C(O)=O)(C)C)C1=CC=C(O)C=C1 MCMMCRYPQBNCPH-WMIMKTLMSA-N 0.000 description 6
- 206010012442 Dermatitis contact Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101100108551 Mus musculus Akr1b7 gene Proteins 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 6
- 208000010247 contact dermatitis Diseases 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000002618 kappa opiate receptor antagonist Substances 0.000 description 6
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 description 6
- 229940005483 opioid analgesics Drugs 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 239000001119 stannous chloride Substances 0.000 description 6
- 235000011150 stannous chloride Nutrition 0.000 description 6
- 238000011725 BALB/c mouse Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- APSUXPSYBJVPPS-YAUKWVCOSA-N Norbinaltorphimine Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C=3C[C@]4(O)[C@]67CCN(CC8CC8)[C@@H]4CC=4C7=C(C(=CC=4)O)O[C@H]6C=3NC=25)O)CC1)O)CC1CC1 APSUXPSYBJVPPS-YAUKWVCOSA-N 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- JSWQDLBFVSTSIW-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine Chemical compound NNC1=CC=CC=C1C(F)(F)F JSWQDLBFVSTSIW-UHFFFAOYSA-N 0.000 description 5
- 210000004100 adrenal gland Anatomy 0.000 description 5
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- WHMJAIHVTRKDSF-UHFFFAOYSA-N isoquinolin-5-ylhydrazine Chemical compound N1=CC=C2C(NN)=CC=CC2=C1 WHMJAIHVTRKDSF-UHFFFAOYSA-N 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 5
- 229940067157 phenylhydrazine Drugs 0.000 description 5
- IQMLCMKMSBMMGR-UHFFFAOYSA-N (4-iodophenyl)hydrazine Chemical compound NNC1=CC=C(I)C=C1 IQMLCMKMSBMMGR-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- UTPHCDAXLJPLCD-UHFFFAOYSA-N ethanol;methanesulfonic acid Chemical compound CCO.CS(O)(=O)=O UTPHCDAXLJPLCD-UHFFFAOYSA-N 0.000 description 4
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- FQJPGBZNJWNVQO-UHFFFAOYSA-N methyl 3-hydrazinylbenzoate Chemical compound COC(=O)C1=CC=CC(NN)=C1 FQJPGBZNJWNVQO-UHFFFAOYSA-N 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- KMMKWMSHGAYLMZ-UHFFFAOYSA-N (2-iodophenyl)hydrazine Chemical compound NNC1=CC=CC=C1I KMMKWMSHGAYLMZ-UHFFFAOYSA-N 0.000 description 3
- FWBRUIYZVDMIRD-UHFFFAOYSA-N (2-phenylphenyl)hydrazine Chemical compound NNC1=CC=CC=C1C1=CC=CC=C1 FWBRUIYZVDMIRD-UHFFFAOYSA-N 0.000 description 3
- FQRZYAIZMAZFMR-UHFFFAOYSA-N (3-iodophenyl)hydrazine Chemical compound NNC1=CC=CC(I)=C1 FQRZYAIZMAZFMR-UHFFFAOYSA-N 0.000 description 3
- UQPKIBHPQJMLMI-UHFFFAOYSA-N (4-phenylphenyl)hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=CC=C1 UQPKIBHPQJMLMI-UHFFFAOYSA-N 0.000 description 3
- YBKWRNDQTRDRTH-UHFFFAOYSA-N 1-(2-hydrazinylphenyl)-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC=C1NN YBKWRNDQTRDRTH-UHFFFAOYSA-N 0.000 description 3
- XMCPOOMOOHPRPH-UHFFFAOYSA-N 1-(3-hydrazinylphenyl)-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC(NN)=C1 XMCPOOMOOHPRPH-UHFFFAOYSA-N 0.000 description 3
- YSXGIFZEOCWUDZ-UHFFFAOYSA-N 1-(4-hydrazinylphenyl)-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=C(NN)C=C1 YSXGIFZEOCWUDZ-UHFFFAOYSA-N 0.000 description 3
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 3
- VINLUGYZXQSLCH-UHFFFAOYSA-N 2,3-dihydro-1h-inden-4-ylhydrazine Chemical compound NNC1=CC=CC2=C1CCC2 VINLUGYZXQSLCH-UHFFFAOYSA-N 0.000 description 3
- TZQWYTNGPYDSEM-UHFFFAOYSA-N 2,3-dihydro-1h-inden-5-ylhydrazine Chemical compound NNC1=CC=C2CCCC2=C1 TZQWYTNGPYDSEM-UHFFFAOYSA-N 0.000 description 3
- BKJCVUVNTNUKOD-UHFFFAOYSA-N 2-(2-hydrazinylphenyl)-n,n-dimethylethanamine Chemical compound CN(C)CCC1=CC=CC=C1NN BKJCVUVNTNUKOD-UHFFFAOYSA-N 0.000 description 3
- JXJNHADVPQSCLY-UHFFFAOYSA-N 2-(2-hydrazinylphenyl)ethanol Chemical compound NNC1=CC=CC=C1CCO JXJNHADVPQSCLY-UHFFFAOYSA-N 0.000 description 3
- JCWLPYMSUGJGQV-UHFFFAOYSA-N 2-(4-hydrazinylphenyl)-n,n-dimethylethanamine Chemical compound CN(C)CCC1=CC=C(NN)C=C1 JCWLPYMSUGJGQV-UHFFFAOYSA-N 0.000 description 3
- JDJSTQXUIQOXKY-UHFFFAOYSA-N 2-(4-hydrazinylphenyl)ethanol Chemical compound NNC1=CC=C(CCO)C=C1 JDJSTQXUIQOXKY-UHFFFAOYSA-N 0.000 description 3
- RKVJQMLJROKZMQ-UHFFFAOYSA-N 2-hydrazinyl-n,n-dimethylbenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=CC=C1NN RKVJQMLJROKZMQ-UHFFFAOYSA-N 0.000 description 3
- CTEZEDIMFASQNI-UHFFFAOYSA-N 2-hydrazinylbenzenesulfonamide Chemical compound NNC1=CC=CC=C1S(N)(=O)=O CTEZEDIMFASQNI-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- SBOSIWQIJOMACM-UHFFFAOYSA-N 3-hydrazinylbenzonitrile Chemical compound NNC1=CC=CC(C#N)=C1 SBOSIWQIJOMACM-UHFFFAOYSA-N 0.000 description 3
- XPKKPVBDOPPWJU-UHFFFAOYSA-N 4-[2-(dimethylamino)ethyl]aniline Chemical compound CN(C)CCC1=CC=C(N)C=C1 XPKKPVBDOPPWJU-UHFFFAOYSA-N 0.000 description 3
- BSEHIVHORVDPLB-UHFFFAOYSA-N 4-hydrazinyl-n,n-dimethylbenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(NN)C=C1 BSEHIVHORVDPLB-UHFFFAOYSA-N 0.000 description 3
- DZUUSHCOMPROCJ-UHFFFAOYSA-N 4-hydrazinylbenzonitrile Chemical compound NNC1=CC=C(C#N)C=C1 DZUUSHCOMPROCJ-UHFFFAOYSA-N 0.000 description 3
- FEFZLHXTFXQMNV-UHFFFAOYSA-N 5,6,7,8,9,10-hexahydrobenzo[8]annulen-3-ylhydrazine Chemical compound C1CCCCCC2=CC(NN)=CC=C21 FEFZLHXTFXQMNV-UHFFFAOYSA-N 0.000 description 3
- MHWCDVDXSXQJKQ-UHFFFAOYSA-N 5,6,7,8,9,10-hexahydrobenzo[8]annulen-4-ylhydrazine Chemical compound C1CCCCCC2=C1C=CC=C2NN MHWCDVDXSXQJKQ-UHFFFAOYSA-N 0.000 description 3
- DDESOTPPLFAWEJ-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-2-ylhydrazine Chemical compound C1CCCC2=CC(NN)=CC=C21 DDESOTPPLFAWEJ-UHFFFAOYSA-N 0.000 description 3
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- LSYDOCJJEJTMGM-UHFFFAOYSA-N ethyl 5-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylate Chemical compound C1=CC=C2CC(C(=O)OCC)CCC2=C1N LSYDOCJJEJTMGM-UHFFFAOYSA-N 0.000 description 1
- JKLGYTSUYIFCAZ-UHFFFAOYSA-N ethyl 8-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylate Chemical compound C1=CC(N)=C2C(C(=O)OCC)CCCC2=C1 JKLGYTSUYIFCAZ-UHFFFAOYSA-N 0.000 description 1
- XFDYTVLGIYJSNX-UHFFFAOYSA-N ethyl 8-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylate Chemical compound C1=CC(N)=C2CC(C(=O)OCC)CCC2=C1 XFDYTVLGIYJSNX-UHFFFAOYSA-N 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
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- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 150000004681 metal hydrides Chemical class 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- STPYUDKGTAYNHQ-UHFFFAOYSA-N methanesulfonic acid;methyl 3-hydrazinylbenzoate Chemical compound CS(O)(=O)=O.COC(=O)C1=CC=CC(NN)=C1 STPYUDKGTAYNHQ-UHFFFAOYSA-N 0.000 description 1
- KEKVVUKKFCVZSL-UHFFFAOYSA-N methyl 2-hydrazinylbenzoate Chemical compound COC(=O)C1=CC=CC=C1NN KEKVVUKKFCVZSL-UHFFFAOYSA-N 0.000 description 1
- VZDNXXPBYLGWOS-UHFFFAOYSA-N methyl 3-aminobenzoate Chemical compound COC(=O)C1=CC=CC(N)=C1 VZDNXXPBYLGWOS-UHFFFAOYSA-N 0.000 description 1
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- URZRWUKJMJVQBP-UHFFFAOYSA-N n,n-dimethyl-2-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=CC=C1[N+]([O-])=O URZRWUKJMJVQBP-UHFFFAOYSA-N 0.000 description 1
- SIAFPFYUZDZDQD-UHFFFAOYSA-N n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=CC([N+]([O-])=O)=C1 SIAFPFYUZDZDQD-UHFFFAOYSA-N 0.000 description 1
- ZCWXRMBVAKOURU-UHFFFAOYSA-N n,n-dimethyl-4-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 ZCWXRMBVAKOURU-UHFFFAOYSA-N 0.000 description 1
- OZBSFHSFPFTCED-UHFFFAOYSA-N n-(cyclopropylmethyl)-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC=CC=C1S(=O)(=O)NCC1CC1 OZBSFHSFPFTCED-UHFFFAOYSA-N 0.000 description 1
- IHTCOFUFTWBICG-UHFFFAOYSA-N n-(cyclopropylmethyl)-3-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)NCC2CC2)=C1 IHTCOFUFTWBICG-UHFFFAOYSA-N 0.000 description 1
- WUJXPCNDIPHZDB-UHFFFAOYSA-N n-(cyclopropylmethyl)-4-nitrobenzenesulfonamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NCC1CC1 WUJXPCNDIPHZDB-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229940005654 nitrite ion Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000003399 opiate peptide Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- XMIAFAKRAAMSGX-UHFFFAOYSA-N quinolin-5-amine Chemical compound C1=CC=C2C(N)=CC=CC2=N1 XMIAFAKRAAMSGX-UHFFFAOYSA-N 0.000 description 1
- RJSRSRITMWVIQT-UHFFFAOYSA-N quinolin-6-amine Chemical compound N1=CC=CC2=CC(N)=CC=C21 RJSRSRITMWVIQT-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Definitions
- the present invention relates to compounds having affinities to ⁇ -opioid receptor.
- ⁇ -opioid receptor relates to analgetic, immune and circulatory systems (especially blood pressure) and ligands having high selectivities to this receptor can be used as analgesics, immunosuppressive agents (employed in organ transplantation (kidney, liver and heart), skin transplantation, treatment of autoimmune diseases (rheumatism, various allergies and collagen diseases) and the like], immunopotentiating agents (anti-tumor agents and anti-virus agents), blood pressure-lowering agents and the like.
- immunosuppressive agents employed in organ transplantation (kidney, liver and heart), skin transplantation, treatment of autoimmune diseases (rheumatism, various allergies and collagen diseases) and the like
- immunopotentiating agents anti-tumor agents and anti-virus agents
- blood pressure-lowering agents and the like.
- Opioid receptors include three types called ⁇ , ⁇ and ⁇ .
- ⁇ -opioid receptor relates various pharmacological effects as mentioned above.
- the number of agonists and antagonists having high selectivities to this receptor is small and the mechanism has not yet been clarified.
- NTI non-peptidic antagonist NTI was discovered by Portoghese (Portoghese, P.S. et al., J. Med. Chem., 31, 281 (1988); 33, 1714 (1990)).
- NTI non-peptidic antagonist NTI
- opioids may possibly be immunopotentiating agents and immunosuppressive agents.
- the present inventors studied influence on immune system by NTI. As a result, it was shown that this compound exhibits immunosuppressive action in vitro and in vivo (Japanese Laid-open Patent Application (Kokai) No. 3-223288). Since currently used immunosuppressive agents have problems in toxicities and side effects, an agent having a low toxicity or having a different mechanism of action is demanded. It is expected that ⁇ -opioid antagonist is one of the candidates thereof.
- opioids relate to flow of calcium ion into cells, which has a relationship with ischemia in brain, and that opioids have brain cell-protecting action.
- use of opioids as a brain cell-protecting agent is more and more expected.
- An object of the present invention is to provide a ⁇ -opioid antagonist having high antagonist activity and receptor selectivity.
- Another object of the present invention is to provide a ⁇ -opioid antagonist having high immunosuppressive action and brain cell-protecting action.
- the present invention provides an indole derivative represented by the formula (I): [wherein R1 represents C1 - C5 alkyl, C4 - C6 cycloalkylalkyl, C5 - C7 cycloalkenylalkyl, aryl, C1 - C3 aralkyl, C4 - C5 trans-alkenyl, allyl, C1 - C3 furan-2-ylalkyl or C1 - C3 thiophene-2-ylalkyl; R2 represents hydrogen, hydroxy, C1 - C5 alkanoyloxy or C1 - C5 alkoxy; R3 represents hydrogen, C1 - C5 alkyl, C1 - C5 alkanoyl or benzyl; R4 represents hydrogen,
- the present invention also provides an immunosuppressive agent, a brain cell-protecting agent, an antiallergic agent and an anti-inflammatory agent comprising as an effective ingredient the indole derivative or the pharmaceutically acceptable acid addition salt thereof according to the present invention.
- the present invention further provides a process for producing the indole derivative or the pharmaceutically acceptable acid addition salt thereof according to the present invention, comprising the step of reaction of a compound of the formula (III): (wherein R1, R2 and R3 represent the same meanings as described above, respectively) with a phenylhydrazine derivative of the formula (IV): (wherein R4, R5 and R6 represent the same meanings as described above, respectively) in the presence of an acid catalyst.
- novel indole derivatives which are ⁇ -opioid antagonists having high selectivities and activities, and phamaceutically acceptable acid addition salts thereof, as well as a process for producing the same, were provided.
- the indole derivatives according to the present invention have excellent immunosuppressive actions, brain cell-protecting actions, antiallergic actions and anti-inflammatory actions.
- Fig. 1 shows the change in antagonist action of compounds 173 and 174 according to the present invention against DPDPE with time, which was determined by calculating Ke value at 15 minutes, 30 minutes and 1 hour from the addition of the test compounds, using MVD.
- Fig. 2 shows the change in antagonist action of compound 174 according to the present invention against DPDPE in scale enlarged by changing the scale of the ordinate in Fig. 1.
- indole derivatives according to the present invention are represented by the above-described formula (I).
- indole derivatives represented by the formula (I) those represented by the following formula (IIa) are preferred, wherein R1, R2, R3 and R4 have the same meanings as described above, respectively, R5 and R6 are bonded to form C4 alkylene with the proviso that one or more hydrogen atoms in the alkylene moiety may be substituted with R10 (wherein R10 represents C1 - C5 alkyl, C1 - C5 alkoxy, C1 - C5 alkanoyl, C1 - C5 hydroxyalkyl, SR7, SOR7, SO2R7 (CH2) m CO2R7, SO2NR8R9, CONR8R9, (CH2) n NR8R9 (wherein m, n, R7, R8 and R9 represent the same meanings as described above, respectively).
- Preferred examples of the acid for forming pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, hydriodic acid and phosphoric acid; organic carboxylic acids such as acetic acid, lactic acid, citric acid, oxalic acid, glutaric acid, malic acid, tartaric acid, fumaric acid, mandelic acid, maleic acid, benzoic acid and phthalic acid; and organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
- hydrochloric acid, phosphoric acid, tartaric acid and methanesulfonic acid are preferred, although not limited thereto.
- specific examples of the compounds according to the present invention include 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-4'-iodo-6,7-2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-6'-iodo-6,7-2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-7'-iodo-6,7-2',3'-indolomorphinan, 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-4'-iodo-6,7-2',3'-indolomorphinan, 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇
- specific examples of the compounds according to the present invention include 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-6'-ethoxycarbonyl-6,7-didehydromorphinano[6,7-b]cyclohexeno[g]indole, 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-7'-ethoxycarbonyl-6,7-didehydromorphinano[6,7-b]cyclohexeno[g]indole, 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-8'-ethoxycarbonyl-6,7-didehydromorphinano[6,7-b]cyclohexeno[g]indole, 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-9'-ethoxycarbonyl-6,7-didehydromorphin
- R1, R2, R3 and R4 represent the meanings described above, respectively, and R5 and R6 independently represent hydrogen, trifluoromethyl, trifluoromethoxy, iodine, cyano, phenyl, C1 - C3 hydroxyalkyl, SR7, SO2R7, (CH2) m CO2R7 (wherein m represents an integer of 0 - 3 and R7 represents C1 - C5 alkyl), SO2NR8R9, CONR8R9, (CH2) n NR8R9 (wherein n represents an integer of 1 - 3, R8 and R9 independently represent C1 - C5 alkyl, C4 - C6 cycloalkyl) or nitro (bonded to one of 4'-, 6'- and 7'-positions), that is, the compounds represented by the formula (Ia) (excluding the case wherein R5 and R6 simultaneously represent hydrogen), and the compounds represented by the formula (II) (
- the solvent examples include alcoholic solvents such as methanol and ethanol; aliphatic acid solvents such as acetic acid and propionic acid; and dipolar aprotic solvents such as DMF and DMSO. Among these, alcoholic solvents and aliphatic acid solvents are preferred, and ethanol and acetic acid are best preferred.
- the acid catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, formic acid and propionic acid. Among these, hydrochloric acid, sulfuric acid and methanesulfonic acid are preferred.
- the reaction may be carried out at 0 - 300 o C, preferably 25 - 150 o C, more preferably 60 - 120 o C.
- the compounds wherein R1, R2 and R4 represent the same meanings as described above, R3 is hydrogen, R5 is (CH2) n NR8R9 (wherein n 1, R8 and R9 represent the same meanings described above), and R6 is hydrogen, that is, the compounds represented by the formula (Id) can also be obtained from the compounds of the formula (I) wherein R1, R2 and R4 represent the same meanings as described above, R3 is hydrogen, R5 is CONR8R9 (wherein R8 and R9 represent the same meanings described above), and R6 is hydrogen, that is, the compounds represented by the formula (Ib).
- the first step is the step for protecting the phenolic hydroxyl group with tert-butyldimethylsilyl group in the presence of a base.
- a base triethylamine, diisopropylethylamine, imidazole and the like may be employed and satisfactory results are usually obtained by using imidazole.
- the solvent halogen-substituted solvents such as methylene chloride and chloroform, and DMF and the like may be employed. Among these, DMF is preferred.
- the reaction temperature range may be between -50 and 150 o C and satisfactory results are usually obtained at 0 - 30 o C.
- the second step is the step for reducing amide to amine and for removing the protective group.
- the reducing agent lithium aluminum hydride, diborane, diisobutylaluminum hydride and the like may be employed, and diborane is best preferred.
- the solvent ether solvents such as ether, THF, DME and dioxane are preferred and satisfactory results are usually obtained by using THF.
- the reaction can be carried out at -50 - 150 o C, and especially good results are obtained at 50 - 100 o C.
- the removal of the protective group is carried out simultaneously when an acid is added for decomposition of the reducing reaction.
- the reaction is carried out by direct addition of an acid to the reaction solution. Examples of the acid used here include hydrochloric acid, sulfuric acid, nitric acid and the like, and hydrochloric acid is best preferred.
- the reaction can be carried out at 0 - 150 o C, and especially good results are obtained at 50 - 100 o C.
- R1, R2, R3 and R4 represent the same meanings as described above
- R5 represents isothiocyanato (bonded to one of 4'-, 6'- and 7'-positions)
- R6 is hydrogen
- the first step is the step for reducing the nitro group to amino group.
- Methods for the reduction include a method wherein hydrogenation is carried out by using a catalyst such as palladium or platinum; a method wherein reduction is carried out by using a metal hydride such as lithium aluminum hydride; a method in which a metal such as iron, tin, zinc or the like and an acid are used; and a method in which the reduction is carried out by using stannous chloride. Satisfactory results are obtained by using stannous chloride.
- a catalyst such as palladium or platinum
- a metal hydride such as lithium aluminum hydride
- a metal such as iron, tin, zinc or the like and an acid are used
- stannous chloride stannous chloride
- the solvent alcohols solvents such as methanol and ethanol are preferred, and ethanol is especially preferred.
- the reaction may be carried out at 0 - 80 o C, preferably 50 - 80 o C.
- the second step is the step for reaction of the amine with thiophosgene to convert the amine to isothiocyanate.
- the solvent two-phase systems between halogen-substituted solvents such as chloroform and methylene chloride, and aqueous sodium hydrogen carbonate solution or dilute hydrochloric acid are preferred, and chloroform-dilute hydrochloric acid is especially preferred.
- the reaction may be carried out at -50 - 60 o C, preferably 0 - 30 o C.
- phenylhydrazine derivatives represented by the formula (IV) [wherein R4 represents the same meanings as described above, R5 and R6 independently represent hydrogen, iodine, trifluoromethyl, trifluoromethoxy, cyano, phenyl, C1 - C3 hydroxyalkyl, SR7, SO2R7, (CH2) m CO2R7 (wherein m represents an integer of 0 - 3, R7 represents C1 - C5 alkyl), SO2NR8R9, CONR8R9, (CH2) n NR8R9 (wherein n represents an integer of 1 - 3, R8 and R9 independently represents hydrogen, C1 - C5 alkyl, or C4 - C6 cycloalkylalkyl) or nitro (bonded to 2- or 3-position), with the proviso that R5 and R6 are not simultaneously hydrogen], commercially available compounds or synthesized products are used.
- the derivative (IVa) wherein R4 is hydrogen is derived from a nitrobenzene derivative (VI) or an aniline derivative (VII) through the route shown in Chart 4.
- the first step is the step for reduction of nitro group to amino group. Similar to the first step in Chart 2, various methods may be employed. Satisfactory results are obtained by employing hydrogenation or the method using stannous chloride.
- the catalyst for hydrogenation platinum oxide, palladium-carbon or the like can be employed and the reaction normally proceeds under 1 atm of hydrogen atmosphere.
- the solvent alcoholic solvents such as methanol and ethanol are preferred and methanol is especially preferred.
- the reaction may be carried out at -20 - 60 o C, preferably 0 - 30 o C.
- the conditions of the reaction employing stannous chloride are the same as the first step in Chart 2.
- the second step is the step for reaction of the product with nitrite ion under acidic condition for conversion of the compound to diazonium ion and for reduction of the resultant to hydrazine.
- the diazotization agent sodium nitrite, potassium nitrite and the like may be employed, and satisfactory results are usually obtained by using sodium nitrite.
- the reaction is carried out using concentrated hydrochloric acid as the solvent. The reaction may be carried out at -30 - 100 o C, preferably -10 - 30 o C, and is usually carried out at 0 o C.
- the reduction may be carried out using stannous chloride, tin, iron, zinc or the like in the presence of an acid, and satisfactory results are usually obtained by using stannous chloride.
- As the solvent concentrated hydrochloric acid is used.
- the reaction temperature is preferably -30 - 50 o C and good results are usually obtained at 0 o C.
- the phenylhydrazine derivative (IVf) wherein R4 represents the same meanings as described above, R5 is CONR8R9 (wherein R8 and R9 represent the same meanings as described above), and R6 is hydrogen can also be synthesized from the phenylhydrazine derivative (IVb) wherein R4 represents the same meanings as described above, R5 is CO2R7 (wherein R7 represents the same meanings as described above), and R6 is hydrogen, by the method shown in Chart 5.
- the first step is the step for protection of hydrazine with tert-butoxycarbonyl group.
- di-tert-butylcarbonate is employed.
- the solvents mixed solvents of an organic solvent-aqueous solvent are employed.
- halogen-substituted solvents such as chloroform and methylene chloride are preferred, and as the aqueous solvent, aqueous sodium hydrogen carbonate solution, aqueous potassium carbonate solution, aqueous sodium hydroxide solution, and aqueous potassium hydroxide solution are preferred. Mixed solvent of chloroform - aqueous sodium hydrogen carbonate solution is especially preferred, although the solvent is not restricted thereto.
- the reaction may be carried out at 0 - 150 o C and satisfactory results are usually obtained at 50 - 100 o C.
- the second step is the step for hydrolyzing the ester under basic condition.
- sodium hydroxide, potassium hydroxide or the like may be employed.
- the third step is the step for condensing the carboxylic acid with amine to form amide.
- the condensing agent DCC, 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloric acid salt and the like are employed. In view of the ease of post-treatment, 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloric acid salt is preferred.
- halogen-substituted solvents such as chloroform, methylene chloride and 1,2-dichloroethane are preferred.
- the reaction may be carried out at 0 - 150 o C, preferably at 20 - 80 o C.
- the fourth step is the step for removing the protective group of hydrazine under acidic condition.
- acid hydrochloric acid, sulfuric acid, nitric acid and the like may be employed, and hydrochloric acid is preferred.
- alcoholic solvents such as ethanol and methanol, ether solvents such as THF and dioxane, and ethyl acetate and the like are preferred, and satisfactory results are usually obtained by using ethyl acetate.
- the reaction may be carried out at -20 - 100 o C, preferably at 0 - 30 o C.
- the free base or the acid addition salt thereof per se may be administered, or the active compound may be administered after mixing with an appropriate excipient such as a stabilizer, buffering agent, diluent, isotonic agent, antiseptic or the like.
- the compound may be formulated into various forms such as injection solutions, sublingual tablets, capsules, suppositories, formulations for oral administration and the like. The dose of administration is appropriately determined based on the object of administration, route of administration and conditions of the patient.
- the active compound in case of injection, 0.0001 - 1 g/day of the active compound is administered, and in case of oral administration, 0.001 - 10 g/day of the active compound is administered.
- the content of the compound of the present invention in a pharmaceutical formulation may be 0.05 - 99%. In case of injection solutions, the content may be 0.5 - 20%, and in case of formulations for oral administration, the content may be 0.1 - 50%.
- 2-(3-nitrophenyl)ethylamine 2-(2-nitrophenyl)ethylamine, 4-nitrobenzylamine, 3-nitrobenzylamine or 2-nitrobenzylamine in place of 2-(4-nitrophenyl)ethylamine, N,N-dimethyl-2-(3-nitrophenyl)ethylamine, N,N-dimethyl-2-(2-nitrophenyl)ethylamine, N,N-dimethyl-4-nitrobenzylamine, N,N-dimethyl-3-nitrobenzylamine and N,N-dimethyl-2-nitrobenzylamine are obtained, respectively.
- the resultant was dried and concentrated and the obtained residue was purified by column chromatography [silica gel; chloroform:methanol:28% aqueous ammonia solution (97:3:0.3)].
- the obtained powder was suspended in methanol and methanesulfonic acid was added to convert the compound to methanesulfonic acid salt.
- the resultant was purified by column chromatography [SEPHADEX LH-20; methanol] to obtain 492 mg of methanesulfonic acid salt of the captioned compound (yield 31%).
- naloxone hydrochloric acid salt By using naloxone hydrochloric acid salt in place of naltrexone hydrochloric acid salt, and by using 4-iodophenylhydrazine, 4-ethoxycarbonylphenylhydrazine, 4-trifluoromethoxyphenylhydrazine, 4-sulfamoylphenylhydrazine, 4-methylsulfonylphenylhydrazine, 4-(N-cyclopropylmethylcarbamoyl)phenylhydrazine, 4-cyanophenylhydrazine, 4-[2-(N,N-dimethylamino)ethyl]phenylhydrazine, 4-(N,N-dimethylamino)methylphenylhydrazine, 4-phenylphenylhydrazine, 4-methylthiophenylhydrazine, 4-(N-cyclopropylmethylsulfamoyl)phenylhydrazine,
- a reaction was carried out in the similar manner as in Example 1 using 1.64 g of naltrexone hydrochloric acid salt, 1.19 g of 3-(2-hydroxyethyl)phenylhydrazine, 0.59 ml of methanesulfonic acid and 33 ml of ethanol.
- the reaction product was purified by column chromatography [silica gel; chloroform:methanol:28% aqueous ammonia solution (90:10:0.1)] to obtain 503 mg (yield 27%) and 1200 mg (yield 60%) of the captioned compounds, respectively.
- naloxone hydrochloric acid salt in place of naltrexone hydrochloric acid salt and by using 3-(2-hydroxyethyl)phenylhydrazine, 3-methylthiophenylhydrazine, 3-(N-cyclopropylmethylsulfamoyl)phenylhydrazine, 3-(N-cyclopropylmethylcarbamoyl)phenylhydrazine, 3-ethoxycarbonylmethylphenylhydrazine, 3-(N,N-dimethylsulfamoyl)phenylhydrazine, 3-cyanophenylhydrazine, 3-trifluoromethylphenylhydrazine, 3-phenylphenylhydrazine, 3-trifluromethoxyphenylhydrazine, 3-sulfamoylphenylhydrazine, 3-iodophenylhydrazine, 3-[2-(N,N-dimethylamino)ethyl)]phenyl
- 2-ethoxycarbonylphenylhydrazine 2-phenylphenylhydrazine, 2-methylthiophenylhydrazine, 2-(2-hydroxyethyl)phenylhydrazine, 2-(N-cyclopropylmethylsulfamoyl)phenylhydrazine, 2-(N,N-dimethylsulfamoyl)phenylhydrazine, 2-sulfamoylphenylhydrazine, 2-ethoxycarbonylmethylphenylhydrazine, 2-(N-cyclopropylmethylcarbamoyl)phenylhydrazine, 2-trifluoromethoxyphenylhydrazine, 2-iodophenylhydrazine, 2-(N,N-dimethylamino)methylphenylhydrazine, 2-[2-(N,N-dimethylamino)ethyl]phenylhydrazine, 1-methyl-1-(2-methylthiophenyl
- naloxone hydrochloric acid salt By using naloxone hydrochloric acid salt in place of naltrexone hydrochloric acid salt, and by using 2-trifluoromethylphenylhydrazine, 2-ethoxycarbonylphenylhydrazine, 2-phenylphenylhydrazine, 2-methylthiophenylhydrazine, 2-(2-hydroxyethyl)phenylhydrazine, 2-(N-cyclopropylmethylsulfamoyl)phenylhydrazine, 2-(N,N-dimethylsulfamoyl)phenylhydrazine, 2-sulfamoylphenylhydrazine, 2-ethoxycarbonylmethylphenylhydrazine, 2-(N-cyclopropylmethylcarbamoyl)phenylhydrazine, 2-trifluoromethoxyphenylhydrazine, 2-iodophenylhydrazine, 2-(N,N
- naloxone hydrochloric acid salt in place of naltrexone hydrochloric acid salt and by using 1-hydrazino-5,6,7,8-tetrahydronaphthalene, 1-hydrazino-5-ethoxycarbonyl-5,6,7,8-tetrahydronaphthalene, 1-hydrazino-6-ethoxycarbonyl-5,6,7,8-tetrahydronaphthalene, 1-hydrazino-7-ethoxycarbonyl-5,6,7,8-tetrahydronaphthalene, 1-hydrazino-8-ethoxycarbonyl-5,6,7,8-tetrahydronaphthalene, 1-hydrazino-5-carbamoyl-5,6,7,8-tetrahydronaphthalene, 1-hydrazino-6-carbamoyl-5,6,7,8-tetrahydronaphthalene, 1-hydrazino-7-carbamoyl-5,6,7,8-tetra
- the mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate solution while cooling the mixture in iced water and chloroform-methanol (3:1) was added to dissolve insoluble matters, followed by separating the generated two layers.
- the resultant was extracted twice with 20 ml of chloroform-methanol (3:1) and the combined organic layers were washed with saturated saline. After drying and concentration, the obtained residue was purified by column chromatography [silica gel; chloroform:methanol (95:5)] to obtain the captioned compound which was then converted to 353 mg of methane sulfonic acid salt (yield 52%).
- This oily product was purified by column chromatography [1 silica gel; chloroform-methanol saturated with ammonia (20:1 ⁇ 15:1); 2 silica gel for flush column chromatography; chloroform-methanol saturated with ammonia (25:1 ⁇ 15:1); 3 SEPHADEX gel; methanol] to obtain 165.2 mg (yield 47%, two steps) of methanesulfonic acid salt of free base of the captioned compound.
- the obtained free base was dissolved in methanol and 0.045 ml of methanesulfonic acid was added thereto. Excess ethyl acetate was then added to precipitate the product to obtain 224.1 mg (yield 46%, two steps) of the captioned compound.
- the obtained residue was purified by column chromatography [silica gel; chloroform-chlorform/methanol (99:1)] to obtain 612 mg of the captioned compound.
- the obtained compound was suspended in methanol and methanesulfonic acid was added to the suspension to convert the compound to methanesulfonic acid salt.
- the salt was purified by column chromatograph [SEPHADEX-LH-20; methanol] to obtain 595 mg of methanesulfonic acid salt of the captioned compound (yield 46%, two steps). 327 methanesulfonic acid salt IR(KBr) ⁇ 1736 cm ⁇ 1.
- the organic layers were combined, dried and concentrated to obtain 542 mg of crude product.
- the obtained crude product was purified by column chromatography [silica gel 30 g; hexane-ethyl acetate-methanol (7:7:1)] to obtain 490.6 mg (yield 90%) of the captioned compound.
- the obtained compound was dissolved in ethyl acetate and 0.065 ml of methanesulfonic acid solution in ethyl acetate was added thereto. The precipitates were collected by filtration and washed with ethyl acetate to obtain 516.7 mg (yield 79%) of methanesulfonic acid salt of the captioned compound.
- the obtained residue was neutralized by adding aqueous saturated sodium hydrogen carbonate solution and the resultant was extracted with chloroform:methanol (4:1). The organic layers were washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated.
- the obtained residue was purified by column chromatography [silica gel; chloroform/methanol/28% aqueous ammonia (50:1:0.1-20:1:0.1)].
- the low polar component was recrystallized from methylene chloride:ethyl acetate and the high polar component was recrystallized from methylene chloride:methanol to obtain two types of isomers 591 and 592 of the captioned compound in amounts of 306 mg and 402 mg, respectively.
- VPD mouse vas deferens
- DPDPE which is a ⁇ -agonist was cumulatively added and IC50 value (the concentration at which the contraction by the electric stimulation is inhibited by 50%) was calculated. Then 100 nM of the test compound was added. Twenty minutes later, DPDPE was begun to be added cumulatively. The ratio of IC50 values in the molar concentration of the test compound necessary for translating the dose-effect curve to the curve of twice dose) and pA2 value were determined. The pA2 value was determined by the method of Shild et al (Shild, H.O., Br. J. Pharmac. Chamotehr., 4, 277 (1949)).
- the logarithm of the test compound (log[test compound]) was plotted along the abscissa and the logarithm of the value obtained by subtracting 1 from the ratio of IC50 values was plotted in the presence and absence of the test compound [ log(dose ratio - 1) ] along the ordinate.
- the pA2 value was determined from the value on the abscissa when the value on the ordinate of the obtained line is 0.
- ⁇ -antagonist activities of the principal compounds are shown in Tables 1 and 2. All of the compounds have high antagonist activities. In particular, compounds 77 , 119 and 190 exhibited activities as high as about 1.3 - 1.6 times that of NTI (Ke: 0.21, pA2: 9.68) which is the compound most widely used at present as a ⁇ -antagonist.
- CPM means cyclopropylmethyl group.
- the compounds of the present invention have very high activities and selectivities, which irreversibly bind to ⁇ -opioid receptor, so that they would be very useful in the future studies of opioids.
- Hartley male guinea pigs were used. After killing the guinea pigs by clubbing, ilea were taken. The inside of the ilea was washed with a nutrient liquid and only longitudinal muscles were peeled off. Using the thus obtained longitudinal muscles, the tests were carried out using the same apparatus as used in the experiment employing MVD.
- U-50488H which is a ⁇ -agonist was cumulatively added and IC50 value was determined. Thereafter, the muscle was well washed with the nutrient liquid. After the contraction reaction became stable, 100 nM of a test compound was added. From 20 minutes after, U-50488H was cumulatively added and the ratio of IC50 values, Ke value and pA2 value were determined in the same manner as in the experiment employing MVD.
- CPM means cyclopropylmethyl group.
- ⁇ -opioid receptor relates to diuresis and protection of brain cells.
- the present inventors have already proved that nor-BNI widely known as ⁇ -antagonist has brain cell-protecting action (Japanese Laid-open Patent Application (Kokai) No. 3-218313). Since the compounds of the invention are also ⁇ -antagonists, it is expected that these compounds have the same actions. Thus, these compounds were tested for the brain cell-protecting actions.
- MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] method. MTT yields a dark blue formazan compound by mitochondria in living cells. This compound was dissolved in isopropanol and absorbance at 570 nm was measured, thereby measuring the number of living cells.
- Cerebral cortex nerve cells of fetal rats of 17 days old were placed in wells of a 96-well plate at a population density of 1 x 105 cells/cm2. Then 10 ⁇ M of a test compound was added and the cells were cultured in 200 ⁇ l of mixed medium of D-MEM/F ⁇ 12 (1:1) for 3 days (37 o C, 5%CO2). In a control group, the medium alone was added. Then 10 ⁇ l of MTT solution in PBS (6mg/ml) was added and the mixture was allowed to react for 3 hours (37 o C, 5% CO2). After removing the culture medium, 100 ⁇ l of isopropanol was added and the absorbance was measured.
- the ratio of the absorbances of the study group and the control group was employed as an index of brain cell-protecting action.
- the results are shown in Table 5. Clear activities were observed with compounds 7 , 9 , 10 and 180 .
- compounds 9 and 180 exhibited activities higher than that of nor-BNI.
- the compounds of the present invention have superior brain cell-protecting action than nor-BNI, and that NTI which is a ⁇ -opioid antagonist has brain cell-protecting action, it is suggested that the compounds having antagonist activities for both ⁇ - and ⁇ -receptors are superior as brain cell-protecting agents.
- CPM means cyclopropylmethyl group.
- the immunosuppressive activities of the compounds of the present invention were examined by suppression of mouse delayed type hypersensitivity.
- mice Male, 7 weeks old mice were used. The mice were classified into groups depending on the body weight, each group consisting of 7 - 8 mice. Each of the mice was sensitized by subcutaneously administering 25 ⁇ l of SRBC (8 x 108 in saline) on the heel of the left hing leg. On day 4 from the sensitization, 25 ⁇ l of SRBC (8 x 109 in saline) was subcutaneously administered on the right footpad so as to induce delayed type hypersensitivity. The difference in the thicknesses of the right footpad before the induction of reaction and 24 hours after the induction of the reaction was employed as an index of the degree of the reaction.
- test compound was dissolved in 10% DMSO-water and was subcutaneously administered everyday from 3 days before the sensitization to the day of induction of the reaction, totally 8 days.
- 10% DMSO-water alone was administered in the same manner.
- the volume of administration was 5 ml/kg in both study groups and in the control group.
- the % suppression of the delayed type hypersensitivity reaction was calculated according to the following equation: wherein A means the difference in the thickness of the right hind leg before and after the reaction in control group, and B means the difference in the thickness of the right hind leg before and after the reaction in the group to which the test compound was administered.
- CPM means cyclopropylmethyl group.
- mice Male, 7 weeks old were used, and each group consisted of 4 - 5 mice.
- the spleen cells (5 x 106) of the donor were subcutaneously administered on the right hing leg and spleen cells (5 x 106) obtained from a mouse of the same line as the recipient mice were subcutaneously administered on the left footpad.
- the thicknesses of the right and left footpads were measured with a dial thickness gage, and the difference in thicknesses of the right and left footpads before the induction of the reaction and 24 hours after the induction of the reaction was employed as the index of the degree of the reaction.
- test compound was dissolved in 10% DMSO-water and was subcutaneously administered everyday from the day of sensitization to the day of induction of the reaction, totally 8 days.
- 10% DMSO-water alone was administered in the same manner.
- the volume of administration was 10 ml/kg in both study groups and in the control group.
- Table 7 Suppression of Delayed Type Hypersensitivity by Indole Compounds (2) Compound R1 X Y % Suppression 2 CPM -(CH2)4- 60 43 CPM SCH3 H 27 119 CPM H CO2C2H5 31 120 CPM H Ph 46 393 CPM CO2C3H7 H 33 591 CPM H SOCH3 16 592 CPM H SOCH3 20 NTI CPM H H 60 CsA 32
- CPM means cyclopropylmethyl group.
- mice Male, 7 weeks old were used, and each group consisted of 4 - 5 mice.
- the spleen cells (5 x 106) of the donor were subcutaneously administered on the right footpad and spleen cells (5 x 106) obtained from a mouse of the same strain as the recipient mice were subcutaneously administered on the left footpad.
- the thicknesses of the right and left footpads were measured with a dial thickness gage, and the difference in thicknesses of the right and left footpads before the induction of the reaction and 24 hours after the induction of the reaction was employed as the index of the degree of the reaction.
- test compound was dissolved in water and 5 x 10 ⁇ 8 mol/mouse was administered into cerebral ventricles. In the control group, water alone was administered similarly. The dose was 5 ⁇ l/mouse in both the study groups and the control group.
- compound 2 according to the present invention exhibited suppressive effect far stronger than NTI, so that it was found that this is a strong immunosuppressant which acts through different mechanism from that of the conventional drugs.
- the mechanism of immunosuppression of the compound of the present invention was examined using delayed type hypersensitivity suppression test using mice from which adrenal glands have been removed.
- mice Male, 7 weeks old were used, and each group consisted of 4 - 5 mice.
- the spleen cells (5 x 106) of the donor were subcutaneously administered on the right footpad and spleen cells (5 x 106) obtained from a mouse of the same strain as the recipient mice were subcutaneously administered on the left footpad.
- the thicknesses of the right and left footpads were measured with a dial thickness gage, and the difference in thicknesses of the right and left footpads before the induction of the reaction and 24 hours after the induction of the reaction was employed as the index of the degree of the reaction.
- the adrenectomy was performed by cutting the back of each recipient mouse under anesthesia with ether before the sensitization and removing the adrenal gland. Sham operation was performed by cutting the back of each recipient mouse but not removing the adrenal gland.
- test compound was dissolved in 10% DMSO-water and was subcutaneously administered everyday from the day of sensitization to the day of induction of the reaction, totally 8 days.
- 10% DMSO-water alone was administered in the same manner.
- the volume of administration was 10 ml/kg in both study groups and in the control groups.
- Delayed type hypersensitivity reaction relates to rejection during organ transplantations and allergy. Since the compound of the present invention suppresses this reaction, it can be used for suppressing the rejection during organ transplantations. Further, the compound has wide uses such as antiallergic agent and anti-inflammatory agent.
- mice Male, 13 - 15 weeks old were used, and each group consisted of 4 mice.
- DNFB 2,4-difluorobenzene
- 0.1% DNFB 50 ⁇ l was sensitized to the clipped skin of the abdominal wall, so as to sensitize the mouse.
- 0.15% DNFB 25 ⁇ l/ear was challenged on closal side of each ear love of each mouse, so as to induce the reaction.
- the compound was administered into cerebral ventricle 30 minutes before the induction.
- the contact dermatitis was detected in terms of the increase in the thicknesses of the ears.
- Compound 2 of the present invention exhibited suppression of 44%, so that it was shown that this compound is effective for allergic dermatitis.
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Abstract
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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JP259841/92 | 1992-09-29 | ||
JP25984192 | 1992-09-29 | ||
JP25984192 | 1992-09-29 | ||
PCT/JP1993/001388 WO1994007896A1 (fr) | 1992-09-29 | 1993-09-29 | Derive indole, procede pour sa fabrication, et son usage medicinal |
Publications (3)
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EP0614898A1 true EP0614898A1 (fr) | 1994-09-14 |
EP0614898A4 EP0614898A4 (fr) | 1994-10-12 |
EP0614898B1 EP0614898B1 (fr) | 2003-05-07 |
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EP93921084A Expired - Lifetime EP0614898B1 (fr) | 1992-09-29 | 1993-09-29 | Derive indole, procede pour sa fabrication, et son usage medicinal |
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US (2) | US6087369A (fr) |
EP (1) | EP0614898B1 (fr) |
JP (1) | JP3605825B2 (fr) |
KR (1) | KR100301093B1 (fr) |
CN (1) | CN1043766C (fr) |
AT (1) | ATE239732T1 (fr) |
AU (1) | AU672033B2 (fr) |
CA (1) | CA2124455C (fr) |
DE (1) | DE69332945T2 (fr) |
ES (1) | ES2199220T3 (fr) |
FI (1) | FI942499A (fr) |
NO (1) | NO941977L (fr) |
TW (1) | TW271440B (fr) |
WO (1) | WO1994007896A1 (fr) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995013071A2 (fr) * | 1993-11-08 | 1995-05-18 | Regents Of The University Of Minnesota | Traitement des troubles immunoregulateurs |
WO1995031463A1 (fr) * | 1994-05-18 | 1995-11-23 | Astra Aktiebolag | Nouveaux composes antagonistes |
WO1996023793A1 (fr) * | 1995-01-30 | 1996-08-08 | Regents Of The University Of Minnesota | Antagonistes du recepteur delta des opioides |
WO1997025331A1 (fr) * | 1996-01-10 | 1997-07-17 | Smithkline Beecham S.P.A. | Derives morphinoides (ii) a heterocycle condense |
EP0805157A1 (fr) * | 1995-09-26 | 1997-11-05 | Toray Industries, Inc. | Derives d'indole et leur utilisation medicinale |
EP0894799A1 (fr) * | 1997-01-16 | 1999-02-03 | Toray Industries, Inc. | Derives d'indolomorphinane et medicaments/remedes preventifs contre les troubles cerebraux |
US5886001A (en) * | 1994-05-18 | 1999-03-23 | Astra Ab | Agonist compounds |
US5994327A (en) * | 1995-11-17 | 1999-11-30 | Astra Ab | Process for the preparation of morphinans |
WO2003063779A2 (fr) * | 2002-01-25 | 2003-08-07 | Regents Of The University Of Minnesota | Agents analgesiques selectifs |
EP1595541A1 (fr) | 2004-05-12 | 2005-11-16 | Alcasynn Pharmaceuticals Gmbh | Utilisation d'antagonistes aux récepteurs opioides pour prévenir et/ou traiter les maladies associées à la cible calcineurine |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2199220T3 (es) | 1992-09-29 | 2004-02-16 | Toray Industries, Inc. | Derivado de indol, procedimiento para su produccion y usos medicinales del mismo. |
EP0911334B1 (fr) * | 1997-03-31 | 2008-05-21 | Toray Industries, Inc. | Derives de quinolinomorphinane et leur usage medical |
US5986141A (en) * | 1998-09-29 | 1999-11-16 | Eastman Chemical Company | Process for the production of cyclopropanemethylamine |
JP4867123B2 (ja) * | 1999-08-24 | 2012-02-01 | 東レ株式会社 | 神経因性疼痛治療剤および神経因性疼痛のモデル動物 |
US8205237B2 (en) | 2000-09-14 | 2012-06-19 | Cox Ingemar J | Identifying works, using a sub-linear time search, such as an approximate nearest neighbor search, for initiating a work-based action, such as an action on the internet |
US7232829B2 (en) | 2001-04-06 | 2007-06-19 | Regents Of The University Of Minnesota | Therapeutic compounds and methods |
US6858619B2 (en) | 2001-05-04 | 2005-02-22 | Amgen Inc. | Fused heterocyclic compounds |
US6809104B2 (en) | 2001-05-04 | 2004-10-26 | Tularik Inc. | Fused heterocyclic compounds |
MXPA05004739A (es) | 2002-11-06 | 2005-08-02 | Tularik Inc | Compuestos heterociclicos fusionados. |
ES2784690T3 (es) | 2013-12-05 | 2020-09-29 | Univ Bath | Nuevos compuestos opioides y sus usos |
Citations (2)
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WO1989000995A1 (fr) * | 1987-07-29 | 1989-02-09 | Regents Of The University Of Minnesota | Antagonistes de recepteurs d'opioides delta |
US5225417A (en) * | 1992-01-21 | 1993-07-06 | G. D. Searle & Co. | Opioid agonist compounds |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3631829A1 (de) * | 1986-09-19 | 1988-07-28 | Hoechst Ag | Klonierung und verwendung des transaminase gens-tyrb |
JP2906654B2 (ja) * | 1989-11-28 | 1999-06-21 | 東レ株式会社 | 免疫抑制剤及びその製造方法 |
JPH04342529A (ja) * | 1991-05-21 | 1992-11-30 | Toray Ind Inc | 抗アレルギー剤 |
US5354863A (en) * | 1992-01-21 | 1994-10-11 | G. D. Searle & Co. | Opioid agonist compounds |
US5352680A (en) * | 1992-07-15 | 1994-10-04 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists to block opioid agonist tolerance and dependence |
ES2199220T3 (es) * | 1992-09-29 | 2004-02-16 | Toray Industries, Inc. | Derivado de indol, procedimiento para su produccion y usos medicinales del mismo. |
US5457208A (en) * | 1993-06-21 | 1995-10-10 | Regents Of The University Of Minnesota | Kappa opioid receptor antagonists |
JP3123080B2 (ja) * | 1995-09-26 | 2001-01-09 | 東レ株式会社 | 「インドール誘導体およびその医薬用途」 |
-
1993
- 1993-09-29 ES ES93921084T patent/ES2199220T3/es not_active Expired - Lifetime
- 1993-09-29 AT AT93921084T patent/ATE239732T1/de not_active IP Right Cessation
- 1993-09-29 DE DE69332945T patent/DE69332945T2/de not_active Expired - Fee Related
- 1993-09-29 CA CA002124455A patent/CA2124455C/fr not_active Expired - Fee Related
- 1993-09-29 EP EP93921084A patent/EP0614898B1/fr not_active Expired - Lifetime
- 1993-09-29 CN CN93114196A patent/CN1043766C/zh not_active Expired - Fee Related
- 1993-09-29 KR KR1019940701818A patent/KR100301093B1/ko not_active IP Right Cessation
- 1993-09-29 JP JP50889694A patent/JP3605825B2/ja not_active Expired - Fee Related
- 1993-09-29 WO PCT/JP1993/001388 patent/WO1994007896A1/fr active IP Right Grant
- 1993-09-29 AU AU48341/93A patent/AU672033B2/en not_active Ceased
- 1993-11-19 TW TW082109756A patent/TW271440B/zh active
-
1994
- 1994-05-27 NO NO941977A patent/NO941977L/no unknown
- 1994-05-27 FI FI942499A patent/FI942499A/fi unknown
-
1998
- 1998-08-18 US US09/135,580 patent/US6087369A/en not_active Expired - Fee Related
-
1999
- 1999-12-22 US US09/469,544 patent/US6291470B1/en not_active Expired - Fee Related
Patent Citations (2)
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WO1989000995A1 (fr) * | 1987-07-29 | 1989-02-09 | Regents Of The University Of Minnesota | Antagonistes de recepteurs d'opioides delta |
US5225417A (en) * | 1992-01-21 | 1993-07-06 | G. D. Searle & Co. | Opioid agonist compounds |
Non-Patent Citations (5)
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995013071A3 (fr) * | 1993-11-08 | 1995-06-08 | Univ Minnesota | Traitement des troubles immunoregulateurs |
WO1995013071A2 (fr) * | 1993-11-08 | 1995-05-18 | Regents Of The University Of Minnesota | Traitement des troubles immunoregulateurs |
WO1995031463A1 (fr) * | 1994-05-18 | 1995-11-23 | Astra Aktiebolag | Nouveaux composes antagonistes |
US5886001A (en) * | 1994-05-18 | 1999-03-23 | Astra Ab | Agonist compounds |
US6136817A (en) * | 1994-05-18 | 2000-10-24 | Astra Ab | Opioid receptor antagonist compounds |
WO1996023793A1 (fr) * | 1995-01-30 | 1996-08-08 | Regents Of The University Of Minnesota | Antagonistes du recepteur delta des opioides |
EP0805157A1 (fr) * | 1995-09-26 | 1997-11-05 | Toray Industries, Inc. | Derives d'indole et leur utilisation medicinale |
EP0805157B1 (fr) * | 1995-09-26 | 2003-06-04 | Toray Industries, Inc. | Derives d'indole et leur utilisation medicinale |
US5994327A (en) * | 1995-11-17 | 1999-11-30 | Astra Ab | Process for the preparation of morphinans |
CN1090190C (zh) * | 1996-01-10 | 2002-09-04 | 史密丝克莱恩比彻姆股份公司 | 杂环稠合的吗啡类衍生物,制备方法和用途 |
WO1997025331A1 (fr) * | 1996-01-10 | 1997-07-17 | Smithkline Beecham S.P.A. | Derives morphinoides (ii) a heterocycle condense |
US6365594B1 (en) | 1996-01-10 | 2002-04-02 | Smithkline Beecham S.P.A. | Heterocycle-condensed morphinoid derivatives (II) |
EP0894799A4 (fr) * | 1997-01-16 | 2001-08-16 | Toray Industries | Derives d'indolomorphinane et medicaments/remedes preventifs contre les troubles cerebraux |
EP0894799A1 (fr) * | 1997-01-16 | 1999-02-03 | Toray Industries, Inc. | Derives d'indolomorphinane et medicaments/remedes preventifs contre les troubles cerebraux |
KR100557804B1 (ko) * | 1997-01-16 | 2006-06-20 | 도레이 가부시끼가이샤 | 인돌로모르피난유도체및뇌장해치료·예방제 |
WO2003063779A2 (fr) * | 2002-01-25 | 2003-08-07 | Regents Of The University Of Minnesota | Agents analgesiques selectifs |
WO2003063779A3 (fr) * | 2002-01-25 | 2005-02-03 | Univ Minnesota | Agents analgesiques selectifs |
EP1595541A1 (fr) | 2004-05-12 | 2005-11-16 | Alcasynn Pharmaceuticals Gmbh | Utilisation d'antagonistes aux récepteurs opioides pour prévenir et/ou traiter les maladies associées à la cible calcineurine |
WO2005107752A2 (fr) * | 2004-05-12 | 2005-11-17 | Alcasynn Pharmaceuticals Gmbh | Utilisation de composes d'antagonistes du recepteur opioide dans la prevention et/ou le traitement de maladies liees a la calcineurine cible |
WO2005107752A3 (fr) * | 2004-05-12 | 2006-06-01 | Alcasynn Pharmaceuticals Gmbh | Utilisation de composes d'antagonistes du recepteur opioide dans la prevention et/ou le traitement de maladies liees a la calcineurine cible |
CN1997369B (zh) * | 2004-05-12 | 2011-12-21 | 阿尔卡森制药有限公司 | 阿片样受体拮抗剂化合物在制备治疗和/或预防对抑制靶向钙调神经磷酸酶敏感的皮肤病的药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
TW271440B (fr) | 1996-03-01 |
EP0614898B1 (fr) | 2003-05-07 |
US6291470B1 (en) | 2001-09-18 |
AU4834193A (en) | 1994-04-26 |
NO941977L (no) | 1994-07-29 |
ES2199220T3 (es) | 2004-02-16 |
KR100301093B1 (ko) | 2001-10-22 |
DE69332945T2 (de) | 2004-05-19 |
DE69332945D1 (de) | 2003-06-12 |
CA2124455A1 (fr) | 1994-04-14 |
WO1994007896A1 (fr) | 1994-04-14 |
CA2124455C (fr) | 2004-09-14 |
US6087369A (en) | 2000-07-11 |
FI942499A0 (fi) | 1994-05-27 |
FI942499A (fi) | 1994-07-27 |
CN1043766C (zh) | 1999-06-23 |
AU672033B2 (en) | 1996-09-19 |
ATE239732T1 (de) | 2003-05-15 |
NO941977D0 (no) | 1994-05-27 |
EP0614898A4 (fr) | 1994-10-12 |
JP3605825B2 (ja) | 2004-12-22 |
CN1092425A (zh) | 1994-09-21 |
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